► Intervertebral disc disease (IVDD) is a naturally occurring disease in dogs that produces a spontaneous injury to the spinal cord. IVDD is characterized by…
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▼ Intervertebral disc disease (IVDD) is a naturally occurring disease in dogs that produces a spontaneous injury to the spinal cord. IVDD is characterized by mineralization of the intervertebral disc nucleus pulposus, which reduces its load bearing capacity and results in high rates of intervertebral disc herniation (IVDH). IVDH is disproportionately present in Dachshunds compared to other breeds, affecting an estimated 1 in 5 Dachshunds during their lifetime (Levine, J. M. et al., 2011). Assessment of injury severity and recovery in animal models is generally performed using a point scale, where subjects are graded according to metrics such as pain perception, joint movement, and limb coordination (Basso et al., 1995; Levine, G. J. et al., 2009; Olby, N. J. et al., 2001). Although these methods provide a general view of recovery, they are unable to quantify metrics such as joint motion/torque and muscle activation/force produced during specific phases of gait. OpenSim is an open source software package that allows users to estimate joint kinematics/torques and muscle forces/activations in a musculoskeletal model, which can be scaled to a subject’s dimensions (Delp et al., 2007). Generic musculoskeletal models have been developed in the OpenSim platform for humans (Delp et al., 1990), cats (Keshner et al., 1997), and rats (Johnson et al., 2008), however to the author’s knowledge no model has been developed for dogs. April 12, 2016 The purpose of the proposed study was to develop a subject-specific neuromusculoskeletal computer model of a healthy dog using OpenSim software (Delp, Anderson et al. 2007) to deduce patterns of muscle activity during locomotion. The long- term goal of this study is to utilize the model to inform rehabilitation strategies to enhance recovery and function in dogs with SCI based upon an improved understanding of muscle activation patterns. Additionally, the ability to characterize muscle activation patterns will provide a tool for quantifying the efficacy of therapeutic interventions in a canine model that could allow for potential therapeutic advancement in both dogs and humans. The specific aims of this study were: 1. To characterize joint kinematics of healthy Dachshunds during walking gait. 2. To compare model-predicted joint kinematics to measured joint kinematics in healthy Dachshunds during walking gait. H1: Pelvic limb joint range of motion of the model-predicted kinematics will not be different from kinematics calculated from marker trajectory data. H2: Measured motion tracking marker trajectories will not be different from virtual model-predicted marker trajectories. 3. To quantify model sensitivity to changes in maximum muscle isometric force. H3: Varying maximum muscle isometric force will affect peak muscle activation. v April 12, 2016 To address these aims, a bilateral 3D model of the bony structures of the pelvis and pelvic limb (femur, tibia/fibula, phalanges, and metatarsals) and muscles was created using computed tomography (CT) imaging data. Parameters for the OpenSim…
Advisors/Committee Members: Bertocci, Gina, Howland, Dena, Howland, Dena, Magnuson, David, Thompson, Angela.

States, G. R. (2015). Development of a neuromusculoskeletal computer model in a chondrodystrophic dog. (Masters Thesis). University of Louisville. Retrieved from 10.18297/etd/2367 ; https://ir.library.louisville.edu/etd/2367

States GR. Development of a neuromusculoskeletal computer model in a chondrodystrophic dog. [Internet] [Masters thesis]. University of Louisville; 2015. [cited 2020 Jun 07].
Available from: 10.18297/etd/2367 ; https://ir.library.louisville.edu/etd/2367.

Council of Science Editors:

States GR. Development of a neuromusculoskeletal computer model in a chondrodystrophic dog. [Masters Thesis]. University of Louisville; 2015. Available from: 10.18297/etd/2367 ; https://ir.library.louisville.edu/etd/2367

► Graphical information has become a critical method for portraying information for education, work and personal tasks and decisions. Unfortunately there are currently limited means…
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▼ Graphical information has become a critical method for portraying information for education, work and personal tasks and decisions. Unfortunately there are currently limited means of providing this information to individuals who are blind or visually impaired: alternate text is frequently missing, and accessible tactile diagrams tend to be time consuming to make and require expertise in order for them to be interpretable (which may be costly to the user and/or impossible to get). The aim of this project is to provide an accessible system to automatically generate tactile graphics for those who need to interpret information contained in visual images. Previous automatic conversion methods have not been especially successful and are not used in normal practice, possibly because they have not taken advantage of current advances in the field of image processing. In the preliminary work, we systematically look at the myriad of image segmentation methods that exist as part of the conversion process. For those techniques, previous researchers have often compared the results to the “gold standard” of human segmentation to evaluate their success. However, there are important difference between this “gold standard” and what is needed for tactile graphics. Key steps by professionals who create tactile diagrams are simplification so that the information is manageable to extract through the tactile sense, elimination of perspective as it is difficult to interpret tactually, and possible spreading of information across multiple diagrams. Planned work is to examine more closely the underlying themes to the myriad of algorithm are relevant for tactile diagrams. Future work, will also involve taking the initially segmented image, simplifying it further by removing “unimportant” detail so that it is manageable by the tactile system and removing perspective based on geometric information found in the image.
Advisors/Committee Members: Dianne Pawluk.

▼ Identification, reconstruction and matching of fragmentary bones are basic tasks required to accomplish quantification and analysis of fragmentary human remains derived from forensic contexts. Appropriate techniques for three-dimensional surface matching have received great attention in computer vision literature, and various methods have been proposed for matching fragmentary meshes; however, many of these methods lack automation, speed and/or suffer from high sensitivity to noise. In addition, reconstruction of fragementary bones along with identification in the presence of reference model to compare with in an automatic scheme have not been addressed. In order to address these issues, we used a multi-stage technique for fragment identification, matching and registration.
The study introduces an automated technique for matching of fragmentary human skeletal remains for improving forensic anthropology practice and policy. The proposed technique involves creation of surfaces models for the fragmentary elements which can be done using computerized tomographic scans followed by segmentation. Upon creation of the fragmentary elements models, the models go through feature extraction technique where the surface roughness map of each model is measured using local shape analysis measures. Adaptive thesholding is then used to extract model features. A multi-stage technique is then used to identify, match and register bone fragments to their corresponding template bone model. First, extracted features are used for matching with different template bone models using iterative closest point algorithm with different positions and orientations. The best match score, in terms of minimum root-mean-square error, is used along with the position and orientation and the resulting transformation to register the fragment bone model with the corresponding template bone model using iterative closest point algorithm.
Advisors/Committee Members: Mohamed R. Mahfouz, Richard D. Komistek, William R. Hamel.

Chronic kidney disease (CKD) has an annual mortality rate of 22% and can cause secondary complications including hypertension, anemia, secondary hyperparathyroidism, and malnutrition. Currently, clinical diagnosis and evaluation of CKD involves blood and urine testing and biopsy. MRI is not currently used to image CKD, but there is an interest in developing MRI techniques to test kidney function. Usually, renal functional MRI refers to single images reflecting tissue oxygenation. Using time series information may offer additional information about changes in kidneys as a result of disease. In this thesis, blood oxygen level-dependent (BOLD) MRI and diffusion weighted imaging (DWI) were used to investigate the effects of breath holding and water loading on kidneys. First, BOLD MRI was used to measure effects of breath holding on BOLD signal intensity. DWI and fractal analysis were used to measure changes in diffusion, perfusion and microcirculation shortly after water loading. Breath holding results showed no effect on temporal BOLD signal intensity in young, healthy subjects. A significant decrease in signal intensity was measured in the kidney of a single subject with impaired renal function. Although the renal BOLD signal was found to have fractal characteristics, no changes were measured using this technique between pre- and post-water loading scans during the time period examined. Because the signal appears to behave fractally, this technique may be a good candidate for similar kidney function studies in the future. DWI also remained unchanged as a result of water loading during the post-water loading time period examined.

► Several studies have shown the impact of mechanical environments on fracture healing. Studies on the low magnitude, high frequency (LMHF) mechanical stimulations (tens of…
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▼ Several studies have shown the impact of mechanical environments on fracture healing. Studies on the low magnitude, high frequency (LMHF) mechanical stimulations (tens of micro-strains and tens of Hz) have demonstrated improved bone regeneration, especially for bone fractures that do not heal properly and developed into delayed unions or non-unions. This type of treatment is often provided as whole-body vibrations with the patient standing on a vibrating platform. While several studies have shown the useful application of LMHF mechanical stimuli in improving bone density but currently available technologies have limited application in fractured bones. The goal of this project is to develop a bone fracture fixation device that utilizes an integrated actuator based on a magnetostrictive material which changes in physical dimension from tens of nanometers to a few microns depending on the strength of an externally applied magnetic field. The strain produced by the magnetostrictive actuator transferred through the fracture fixation device acts directly on the fracture defect region, resulting in localized loading. The electromagnetic driving system for the magnetostrictive actuator remains outside the body and produces wireless mechanical actuations. This externally controlled mechanical loading can help in investigating the effect of various types of mechanical stimulus on bone healing. Specifically, this project will focus on osteogenesis in critically-sized segmental bone defects in rats, an established animal model in bone regeneration studies. The focus of this project is to (1) develop a device that can generate variable mechanical loads on segmental bone defects in rats and (2) to conduct an in vivo study assessing the effects of augmented mechanical loading on osteogenesis.
Advisors/Committee Members: Keat Ghee Ong.

► Objective: The goal of this study was to investigate the effects of different dietary fatty acids in the context of diet-induced obesity on bone…
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▼ Objective: The goal of this study was to investigate the effects of different dietary fatty acids in the context of diet-induced obesity on bone and cartilage in the humerus. It is known that obesity increases the severity of injury-induced osteoarthritis in the knee, however it is not fully understood what pathological changes have occurred due to diet alone1. Additionally, while it is known that shoulder osteoarthritis has a link to obesity, the alterations in this joint are incompletely described.
Methods: In order to examine diet-induced changes in both bone and cartilage, this research utilized mice that had been previously fed diets high in saturated fat (SF), omega-6 fatty polyunsaturated fatty acids (ω-6 PUFA) or omega-3 polyunsaturated fatty acids (ω-3 PUFA) for an earlier study1. Humeral heads were obtained for testing. Analysis for bone morphometry, bone mineral density, cartilage micro-scale mechanical properties using atomic force microscopy, and histological grading was performed.
Results: Differences in bone morphology and mineral density were seen between diet groups. The high-fat diets in general showed decreased bone quality with the ω-3 PUFA diet being partially protected. Micro-scale cartilage stiffness and overall modified Mankin scores showed no diet-dependence.
Discussion: This study showed that specific types of fatty acids differentially alter bone morphology and mineral density, with no observable changes in the articular cartilage. These findings suggest that in the shoulder, diet-induced obesity by itself may not be a risk factor for osteoarthritis, but may result in other musculoskeletal changes.
Advisors/Committee Members: Farshid Guilak, Spencer Lake
Amit Pathak.

Votava, L. (2018). The Role of Obesity and Dietary Fatty Acid Content in Regulating Humeral Bone and Cartilage Homeostasis. (Thesis). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/eng_etds/353

Note: this citation may be lacking information needed for this citation format:Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Votava, Lauren. “The Role of Obesity and Dietary Fatty Acid Content in Regulating Humeral Bone and Cartilage Homeostasis.” 2018. Thesis, Washington University in St. Louis. Accessed June 07, 2020.
https://openscholarship.wustl.edu/eng_etds/353.

Note: this citation may be lacking information needed for this citation format:Not specified: Masters Thesis or Doctoral Dissertation

Votava L. The Role of Obesity and Dietary Fatty Acid Content in Regulating Humeral Bone and Cartilage Homeostasis. [Internet] [Thesis]. Washington University in St. Louis; 2018. [cited 2020 Jun 07].
Available from: https://openscholarship.wustl.edu/eng_etds/353.

Note: this citation may be lacking information needed for this citation format:Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Votava L. The Role of Obesity and Dietary Fatty Acid Content in Regulating Humeral Bone and Cartilage Homeostasis. [Thesis]. Washington University in St. Louis; 2018. Available from: https://openscholarship.wustl.edu/eng_etds/353

Note: this citation may be lacking information needed for this citation format:Not specified: Masters Thesis or Doctoral Dissertation

► Breast cancer is the most common cancer in women worldwide, and is the second leading cause of cancer-related death in spite of significant advances…
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▼ Breast cancer is the most common cancer in women worldwide, and is the second leading cause of cancer-related death in spite of significant advances in treatment and emphasis on early diagnosis. While treatment of localized disease is often successful, metastatic breast cancer, especially of the triple negative molecular subtype, carries a much poorer prognosis. The significant role of the immune system in the progression from localized to metastatic disease is becoming more and more appreciated. Tumor escape from immune surveillance and immune suppression in the tumor microenvironment have become therapeutic targets in addition to the traditional goals of directly killing tumor cells. A number of immune therapeutic strategies have been proposed and tested, but few have seen clinical application in the treatment of breast cancer. The development of successful breast cancer immunotherapeutic strategies depends on the rapid identification of immunogenic antigens, timely delivery of these antigens by the optimal vehicle to induce a robust immune response, and appropriate combination with other therapies such as adjuvants, innate immune therapies, and the current standard-of-care treatments. This will allow for more comprehensive targeting of the breast cancer immune regulatory network and likely lead to improved therapeutic success. In the following experiments, two immune therapies which address elements of this multipronged approach will be investigated. The models in which these therapies are tested for gross phenotypic effect are intended to bring basic murine models of experimentation closer to the patterns of future clinical application. The first of these
therapies is emodin, a natural, small molecule compound derived from several Chinese herbs. Its immune modulatory properties have been demonstrated in a number of disease models, but our lab was the first to show that it is capable of attenuating breast cancer progression by blocking the interactions between tumor-associated macrophages and cancer cells. Here emodin is tested as an adjuvant therapy following primary tumor surgical removal for the purpose of preventing metastatic recurrence in a model of murine triple negative breast cancer. We show that trough interfering with TGF-β1 signaling, emodin is capable of decreasing the ability of tumor cells to invade and establish themselves at metastatic sites, thereby reducing metastatic recurrence and increasing overall survival. In addition to its ability to disrupt the reciprocal signaling between tumor cells and macrophages, emodin’s low cost and proven low toxicity make it a promising innate immune therapy. The second therapeutic strategy focuses on improving the effectiveness of dendritic cell-based therapeutic cancer vaccines. Our lab was the first to reveal the role of microRNA-155 (miR155) as a key regulator of dendritic cell function. Our previous work has shown that total-body knockout of miR155 increased both tumor growth and metastasis in an orthotopic model of murine breast cancer. Our…
Advisors/Committee Members: Daping Fan.

► Cytotoxic chemotherapy is used for the frontline treatment of most types of cancer but is associated with significant toxicity due to the lack of cell…
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▼ Cytotoxic chemotherapy is used for the frontline treatment of most types of cancer but is associated with significant toxicity due to the lack of cell specificity of these drugs. Newer treatment strategies, such as polymeric drug delivery vehicles that preferentially accumulate in tumors via the EPR effect and oncolytic adenoviruses that replicate conditionally in tumor cells, can reduce the adverse side effects associated with systemic anti-cancer treatments. However, there remain numerous barriers to the successful clinical translation of these therapeutics. Part I focuses on the diffusional barriers to drug delivery to solid tumors. In Chapter 1, we investigate tight junction-opening proteins as a means to enhance nanoparticle penetration into tumors. Part II describes the development of polymer nanostructures for anti-cancer drug delivery. Chapter 2 summarizes the major design parameters for drug delivery to tumors and introduces controlled living polymerization as a synthetic tool. Chapters 3 and 4 describe the synthesis of polymeric drug carriers with a novel sunflower-like architecture. Part III focuses on methods to improve the safety of adenoviruses for cancer gene therapy. Chapter 5 provides an overview of adenovirus pharmacology and current modification strategies, while Chapter 6 describes a new approach to developing materials that can shield adenoviruses against immune recognition. Finally, Chapter 7 summarizes the major findings of this work and concludes with recommendations for future directions.
Advisors/Committee Members: Pun, Suzie H (advisor).

► Intracellular pathogens are a major cause of global morbidity and mortality due to their complex and intricate ability to replicate within host cells while evading…
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▼ Intracellular pathogens are a major cause of global morbidity and mortality due to their complex and intricate ability to replicate within host cells while evading the innate immune defense system. Many intracellular pathogens, such as F. tularensis and B. pseudomallei, are highly infectious and can cause severe and fatal diseases. They are designated as Tier 1 select agents by the Centers for Disease Control and Prevention due to their high infectivity and mortality, transmission by pulmonary route of infection, and potential development as a bioweapon. Current antibiotics are limited by poor pharmacokinetic properties, and consequently require high frequency dosing at high concentrations to show promising clinical success. The physicochemical properties may also limit the route of administration of drugs – a critical factor to consider when select target tissues are of importance. To date, intravenous administration followed by oral tablets are the common routes of administration to deliver drugs; however, in a mass casualty setting, intravenous injections may not be practical. Therefore, new strategies are needed to improve the effectiveness of antibiotics in treating intracellular pulmonary infections. This work utilizes RAFT polymerization techniques to explore synthetic multivalent glycopolymer prodrug systems. Prodrugs are inactive forms of the drug, but when administered undergo hydrolysis to release the pharmacologically active drug. We hypothesized that engineering mannose glycopolymer prodrugs to target the macrophage mannose receptor on alveolar macrophage cells would eradicate or minimize bacterial replication and allow for better protection against intracellular infections. We demonstrated that mannose polymeric prodrug systems provided significantly improved protection against intracellular F. novicida infection in mice challenge models compared to free antibiotic. When intratracheally administered to the lungs of mice in a prophylactic setting, poly(Man-co-CTM) improved survival in 50% of the mice and in a post-infection treatment setting, the survival of mice increased to 87.5%. In both studies, mice treated with free antibiotics remained ineffective. We also show that these results are due to the improved pharmacokinetic and pharmacodynamic properties of ciprofloxacin, in which targeted mannose polymer prodrugs had more than double elimination half-life time in the lungs compared to non-specific polymer prodrugs. We are excited about the promising results of the work presented here, but even more so at the modularity of the prodrug system such that it can be expanded and fine-tuned to be utilized for other diseases and applications.
Advisors/Committee Members: Ratner, Daniel M (advisor).

► The functional effects of mutations associated with cardiomyopathies generally suggest that the Ca2+ responsiveness of the myofilament was affected. This functional change appears to be…
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▼ The functional effects of mutations associated with cardiomyopathies generally suggest that the Ca2+ responsiveness of the myofilament was affected. This functional change appears to be independent of which protein contains the mutation and therefore indicates that the altered Ca2+ sensitivity could be a critical or causative component of disease expression and progression. However, the correlation underlying this functional change with the disease phenotype is still unclear. Thus, in this work a series of single amino acid-substituted cardiac troponin C (cTnC) variants with altered Ca2+ binding affinities were studied to determine how they influence the Ca2+ activation pathway in myofilament contraction and whether this change in Ca2+ binding will result in adaptive changes in intact cardiomyocytes. These variants have not been identified as associated with any cardiomyopathies and therefore may eventually provide clues as to whether altered Ca2+ signaling of myofilament contraction is causal or an adaptive response in diseased hearts. Firstly, we sought structural and mechanistic explanations for the increased/decreased Ca2+ sensitivity of contraction for the cTnC variants using an array of biophysical techniques. The properties of these cTnC variants were characterized by determining their effects on Ca2+ binding ability, cTnC-cTnI interaction and their modulation by PKA phosphorylation in solution, and their structural alterations using molecular dynamic simulations. We found that cTnC variants have different effects on both binding of Ca2+ and cTnI to cTnC, and they also respond differently upon PKA phosphorylation. MD simulations show, for the first time, that cTnC variants could disrupt crucial hydrophobic interactions so that the closed form of cTnC or the Ca2+ binding loop is destabilized. The findings emphasize the importance of the regulatory domain of cTnC's conformation in the regulation of contraction and suggest that mutations in cTnC that alter myofilament Ca2+ sensitivity can do so by modulating Ca2+ and cTnI binding. Secondly, the functional capacity of the Ca2+ desensitizing variants was characterized by expressing them in cardiomyocytes using adenovirus. Additionally, we demonstrate that engineered cTnC variants can correct the disease-induced abnormal Ca2+ binding sensitivity. Our study provides insights for the development of novel therapeutic strategies for the treatment of cardiomyopathies.
Advisors/Committee Members: Regnier, Michael (advisor).

► Influenza is a serious public health concern and new therapeutics that protect against this highly adaptable virus are urgently needed. For this dissertation my efforts…
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▼ Influenza is a serious public health concern and new therapeutics that protect against this highly adaptable virus are urgently needed. For this dissertation my efforts were focused on creating and improving de novo designed small proteins that bind to the influenza surface protein Hemagglutinin (HA) and mimic the binding interaction of neutralizing antibodies. These designed proteins were aimed at a highly conserved stem region targeted by some neutralizing antibodies that can inhibit viral membrane fusion. While parts of the stem region are highly conserved within the two main Influenza groups (I and II) differences between the groups make engineering a broad intergroup binder difficult. New high throughput experimental and computational methods were developed which allowed for the testing and design of tens of thousands of new proteins to achieve these goals. Furthermore, newly developed proteins were designed to be small and hyperstable in order to be more ideal therapeutics.
Advisors/Committee Members: Baker, David (advisor).

► Today, more than 900,000 patients in the United States live with end-stage renal disease, with many more suffer from poor renal regeneration1. Current methods commonly…
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▼ Today, more than 900,000 patients in the United States live with end-stage renal disease, with many more suffer from poor renal regeneration1. Current methods commonly use synthetic tissue-engineered constructs to deliver cells, drugs, or as scaffolds for reconstruction of injured tissues2, 3, 4, 5, 6. However, these constructs usually lack vascularization in vivo, and have poor nutrient diffusion abilities that limit their effectiveness7. On the other hand, we have found that extracellular matrix (ECM) hydrogels can be used as scaffolds to facilitate the repair and reconstruction of various tissues. The objective of this study is to fabricate and characterize the mechanics and cell response in vitro of ECM hydrogels prepared from decellularized human kidney tissues. Our preliminary data indicate that Sodium dodecyl sulfate (SDS) decellularization of human kidney tissue sections gives the most optimal results in terms of cellular material removal and ECM structure preservation; decellularized human kidney ECM, when mixed with collagen gel on a 1:1 ratio, shows similar mechanical properties as commonly used type I collagen gel. These data suggest that decellularized human kidney ECM hydrogels are able to provide the structural support necessary for cellular activities. Given these findings and the fact that ECM hydrogels are derived from naturally occurring kidney materials, I hypothesize that decellularized human kidney ECM hydrogel is able to not only provide structural support for cell growth and proliferation, but also to enhance bioactivity and vascularization. To test this hypothesis, I performed angiogenesis and tubulogenesis studies by seeding human umbilical vein endothelial cells and human kidney microvascular endothelial cells onto or in the decellularized human kidney ECM hydrogel as well as type I collagen gel.
Advisors/Committee Members: Zheng, Ying (advisor).

► Medical and biological research is progressing at an astonishing rate, with an increasing emphasis on the understanding of complex biological systems. At the heart of…
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▼ Medical and biological research is progressing at an astonishing rate, with an increasing emphasis on the understanding of complex biological systems. At the heart of this revolution has been the development of modern researching technologies, especially those that take more biological measurements, with increasing sensitivity and precision, at higher speed and lower cost. For example, immunomagnetic separation has become an essential tool for high throughout and low cost isolation of biomolecules and cells from heterogeneous samples. However, as magnetic selection is essentially a "black-and-white" assay, its application has been largely restricted to single-target and single-parameter studies. This document describes the development of an immunomagnetic separation technology that can quickly sort multiple targets at high yield and purity using selectively displaceable DNA linkers. Overall, this work provides strong evidence for the benefits of this approach for experiments requiring multiplexed immunomagnetic separation, can be readily adopted for specific applications requiring high throughput selection of multiple targets, and further adapted for selection of a single target based on multiple surface epitopes.
Advisors/Committee Members: Gao, Xiaohu (advisor).

► Vibrotactile feedback offers a unique opportunity to augment or reconstruct impaired tactile sensations, whether that be in the form of enhancing prosthetics or specialized…
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▼ Vibrotactile feedback offers a unique opportunity to augment or reconstruct impaired tactile sensations, whether that be in the form of enhancing prosthetics or specialized protective clothing. Important information about temperature and object slippage serve to endanger the human operator or equipment. This thesis presents three experiments which investigate amplitude modulated vibrotactile signals as a scalar dimension of roughness, the effect those signals and their locations (finger pad, forearm, bicep) have on the performance of two tasks: the sensing of temperatures simulated by vibrotactile signals and gripping an object of simulated surface texture. The results show task performance increase when the feedback and site of action are co-located for sensory tasks and decrease for manipulatory tasks.
Advisors/Committee Members: Dianne T.V. Pawluk.

► Mammary epithelial cells are highly efficient secreting cells. With genetic engineering, the uses of these cells could be endless. Research is being conducted…
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▼ Mammary epithelial cells are highly efficient secreting cells. With genetic engineering, the uses of these cells could be endless. Research is being conducted on these cells to determine their full potential to the biotech industry.
This paper investigates whether bovine epithelial mammary cells can survive in glutaraldehyde-treated gelatin tubes in an operating bioreactor. Many bioreactors were developed and tested to suit the needs of the cells. Procedures were created and carried out to ensure sterility of the bioreactors. Bovine mammary epithelial cells were implanted in the bioreactors and samples of their growth were taken over time.
Advisors/Committee Members: Dr. Robert Crockett.

► The goal of this study was to compare the morphological and hemodynamic characteristics of normal and remodeled vascular networks in the mouse gracilis muscle. To…
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▼ The goal of this study was to compare the morphological and hemodynamic characteristics of normal and remodeled vascular networks in the mouse gracilis muscle. To this end, previously developed models to assess flows and vascular branching were used to assess the normal and remodeled microcirculatory networks. The analysis revealed that the average individual vessel flow rates for vessels of similar caliber and total volumetric flow rates in the networks do not change for vessels of the same caliber after remodeling. Connectivity changes and average diameters primarily change in the larger arterioles after remodeling. A few correlations could be made between architectural and flow properties, however, further modifications in the analysis methods can make future correlations more effective. In order to improve the analysis a parameter sensitivity analysis tool (PSAT) was developed. The PSAT is helpful in teasing apart the individual effects of morphological parameters such as vessel connectivity, vessel diameters, and vessel lengths. In future, another important component that allows the investigator to exclusively alter vessel quantities for all the orders can be added to improve the PSAT.
Advisors/Committee Members: Trevor R. Cardinal.

► Coronary artery disease (CAD) is a common cause of sudden cardiac death. Much of the disease is not completely understood, which makes treatment and prevention…
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▼ Coronary artery disease (CAD) is a common cause of sudden cardiac death. Much of the disease is not completely understood, which makes treatment and prevention difficult. Many researchers are using technology, such as advanced imaging techniques and finite element analysis, to better understand the disease. While there is much progress being made to look at the analysis of actual excised diseased arteries, there is still not a standardized model to predict the future of any one lesion. The purpose of this study is to explore the possibility of creating a standardized model to predict the mechanical stability of the fibrous cap due to lipid content in atherosclerotic lesions.
Advisors/Committee Members: Robert Crockett, PhD.

► Crouch gait a progressively degrading gait deviation associated with the neurological disorder cerebral palsy. If left untreated it can lead to anterior knee pain and…
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▼ Crouch gait a progressively degrading gait deviation associated with the neurological disorder cerebral palsy. If left untreated it can lead to anterior knee pain and a loss of ambulation. At present there exists no agreed upon metric for determining the surgical procedures used to treat crouch gait and there is insufficient means to analytically compare the results of different procedures. The aims of this thesis work were to create a pipeline to transform a patient’s gait analysis data into a finite element model, develop a model of sufficient complexity to evaluate a range of outcomes by which to judge the efficacy of a surgical procedure, analyze the change between pre- and post-operative models and the changes between models with different surgical procedures, and to quantify the impact of varying different surgical parameters.
A generic lower limb rigid body musculoskeletal model was developed and used in conjunction with patient-specific static and dynamic motion capture to create scaling factors and joint kinematics, respectively. The musculoskeletal model was scaled and converted into a finite element model. This lower torso model was integrated with a detailed finite element model of the knee joint including patella, femur and tibia heads, associated articular cartilage, patellofemoral ligaments, patellar tendon, and quadriceps tendons. This type of combined finite element model was created for each patient, pre- and post-operatively, for a series of patient’s treated for crouch gait at Children’s Hospital Colorado. Each model was modified to replicate the surgical procedure(s) that each individual patient underwent. Comparison between pre- and post-operative models show significant improvement in tibiofemoral flexion-extension and patellar articular cartilage stress in post-operative models.
In order to assess the effect of surgical parameters on muscle efficiency, the finite element model was modified such that tibiofemoral flexion-extension was controlled by adaptive muscle forces calculated using a proportional-integral feedback control system. The feedback system adjusted quadriceps and hamstrings forces to try and meet a target flexion profile. A feedback control model was created for three patients; subsequently, each model was modified to run multiple simulations with modified surgical procedures and parameters. The models were modified to include distal femoral extension osteotomy procedures of 0º, 15º, or 30º, or patella tendon advancement procedures with 0 cm, 1 cm, or 2 cm shortening. The muscle forces needed to reach the target kinematics were compared. Further simulations are required to identify clear links between surgical decisions and patient-specific parameters, but the developed model shows promise for future studies both for crouch gait and other musculoskeletal pathologies.

► Particle Image Velocimetry (PIV) is an optical technique used for the visualization of fluid flow. PIV can be combined with other techniques to enhance…
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▼ Particle Image Velocimetry (PIV) is an optical technique used for the visualization of fluid flow. PIV can be combined with other techniques to enhance the analysis of fluid flow. A novel far-field plasmonic resonance enhanced nanoparticle-seeded Particle Image Velocimetry (nPIV) has been demonstrated to measure the velocity in a micro channel. Chemically synthesized silver nanoparticles have been used to seed the flow. By using Discrete Dipole Approximation (DDA), plasmonic resonance enhanced light scattering has been calculated for spherical silver nanoparticles with diameters ranging from 15 nm to 200 nm in two media: water and air. The diffraction-limited plasmonic resonance enhanced images of silver nanoparticles at different diameters have been recorded. By using standard PIV techniques, the velocity within the micro channel has been determined from the images collected.
The plasmonic resonance effects of nanoparticles from different media as compared to metal nanoparticles are also examined. Localized Surface Plasmon Resonance (LSPR) effects by naturally occurring Chinese yam particles are observed and quantified. Chinese yam particles are found by an atomic force microscope and a high-speed optical dark-field microscope. The particles with diameters greater than 200 nm are found to contribute most to UV-Vis absorption. LSPR effects of silver nanoparticles by the Chinese yam particles lead to the red shift of the extinction peaks of the silver nanoparticles. The wavelength shifts are quantitatively predicted based on DDA of the LSPR effects, which are sensitive to the local dielectric constant changed by the Chinese yam particles. This finding may open a new avenue to detect the biological sub-micron particles or virus in solution.
PIV gives a new perspective on fluid flow that is otherwise difficult to see. An application of PIV studying the flagella movement of GiardiaLamblis trophozoites is examined. Standard PIV techniques are employed using a combination of high-contrast CytoViva ® imaging system to capture the images at high speeds and the Insight 3G software to measure the speed and direction of fluid motion generated by the microscale flagella. The PIV images illustrate how the flagella of the Giardia interact with each other and how they move in their environment.
Advisors/Committee Members: Zhili Zhang, Xiaopeng Zhao, Mingjun Zhang.

► Fe3O4 [Magnetite] nanoparticles have magnetism that differs greatly from their bulk counterparts. Whereas bulk Fe3O4 is a ferrimagnet, single-domain Fe3O4 nanoparticles have been found…
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▼ Fe3O4 [Magnetite] nanoparticles have magnetism that differs greatly from their bulk counterparts. Whereas bulk Fe3O4 is a ferrimagnet, single-domain Fe3O4 nanoparticles have been found to be superparamagnetic. This allows for increased magnetization of the nanoparticles compared to the bulk when in a magnetic field. For most paramagnets, magnetization requires applied fields of a few Tesla at low temperatures. This is achievable through the application of superconducting magnets. In superparamagnets, the high susceptibility of the particles allows magnetization through a Nd-Fe-B permanent magnet at room temperature. This is caused by an increased number of magnetic atoms within the particles, which greatly increases susceptibility of the particles. 57Co [Cobalt-57] Mössbauer Spectroscopy allows the probing of the internal environment of an iron nucleus, which gives insight into the magnetic properties of the Fe3O4 nanoparticles.
Advisors/Committee Members: Jacqueline A. Johnson, Silke Hecht, Claudia Rawn.

► Vehicles driven off-road damage the soil and vegetation on the terrain, which can cause soil erosion and degradation of the landscape. This type of…
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▼ Vehicles driven off-road damage the soil and vegetation on the terrain, which can cause soil erosion and degradation of the landscape. This type of damage occurs on military installations due to training. Military training lands must be managed in an attempt to minimize the overall impacts of training on the terrain. The Army Training and Testing Area Carrying Capacity (ATTACC) is a model used by the U.S. Army to manage their training lands. Methods of determining the impacts produced by a vehicle and subsequent vegetative recovery have been used at Fort Lewis, WA for the Light Armored Vehicle (LAV). The LAV is an eight-wheeled vehicle with a maximum curb weight of approximately 14,000 kg. In June of 2003, the vehicle was operated in spiral patterns (five high-speed and five low-speed), and the impacts of the vehicle were assessed at this time. Measurements were taken at 13-20 points along each of the 10 spirals. The impact measurements taken at each point were disturbed width and impact severity. The impacts were reassessed after six months and one year to determine recovery from the initial damage. Different types of impacts (imprint, scrape, combination, and pile) were determined based on the characteristics of the damage produced. The recovery of these different impact types was also assessed.
The study site at Fort Lewis was found to have an overall vegetative recovery of 43% after one year, but the different impact types varied in the amount of recovery. Imprint impact types had an almost complete recovery of 74%, while the scrape and combination showed little recovery (11% and 22%, respectively) after one year. The pile also showed a high recovery of 54%. Areas where the vehicle was operated at low speeds showed high recovery (78%). Recovery was much lower (29%) for areas where the vehicle was operated at high speeds. The damage produced was higher and recovery lower when the vehicle was turning sharply.
The data produced by this study will be useful in managing the training with LAVs at Fort Lewis by implementation into the ATTACC model. Further study must be done to determine when these impacts would be fully recovered from the damage. The results found in this study are only applicable to the LAV and Fort Lewis. Other vehicles produce different impacts, and other locations have different climates, soils, and vegetation types that would respond differently to vehicle impacts. The methods used in this study can be utilized at other locations and with different vehicles to provide applications to more sites and a wider variety of vehicles.
Advisors/Committee Members: Paul Ayers, Daniel Yoder, Joanne Logan.

► As implantable medical devices are being used more often to treat medical problems for which pharmaceuticals don’t suffice, it is important to understand their…
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▼ As implantable medical devices are being used more often to treat medical problems for which pharmaceuticals don’t suffice, it is important to understand their interactions with commonly used medical modalities. The interactions between medical implants and Magnetic Resonance Imaging machines have proven to be a risk for patients with implants.
Implanted medical devices with elongated metallic components can create harmful levels of local heating in a Magnetic Resonance Imaging (MRI) environment [1]. The heating of a biological medium under MRI is monitored via the Specific Absorption Rate (SAR). SAR, defined as power absorbed per unit mass (W/kg), can be calculated as , where σ is electrical conductivity of the medium in units of , |E| is the magnitude of the applied electric field in units of , and ρ is the density of the medium in units of . For continuous, uniform power deposition this can be measured experimentally as a rise in temperature over time (∆T/t), where c is the specific heat capacity of the medium in units of. To understand the SAR induced in-vivo, a phantom (Figure 2.10) is used to conduct in-vitro experiments, as it provides a controllable and repeatable experimental setup.
In order to experiment in the phantom, an understanding of the background SAR distribution and in turn the exposure field distribution of the phantom is required as per the ASTMF2182-09 standard [2]. In this work, the background SAR distribution of an ASTM standard torso phantom is measured and studied via fiber optic thermometry. The measurements are compared with an electromagnetic model simulated via FDTD, demonstrating agreement between 10-25%. A custom exposure and data collection setup (including oscilloscope, function generator, RF amplifier, directional coupler, and Neoptix Omniflex Fiber Optic Thermometry system) was integrated and automated using NI LabView.
The purpose of this thesis is to map the field distribution in a torso phantom under RF exposure from a 64 MHz MRI RF Birdcage, compare the results to an electromagnetic simulation, and finally conclude the accuracy of this method for field measurements in a standard torso phantom. Understanding the capabilities and accuracy of the fiber optic thermometry method will ultimately allow researchers to successfully apply this method to monitor background fields in their respective experimental setups (related to MRI implant heating) and understand its limitations.
Advisors/Committee Members: Dennis Derickson.

► Membranes and membrane-associated components are the target of approximately 60% of the current drugs, of synthetic materials, such as polymers, which are used for…
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▼ Membranes and membrane-associated components are the target of approximately 60% of the current drugs, of synthetic materials, such as polymers, which are used for drug delivery purposes and of other biomolecules, such as endotoxins, which gain entry into the cell by disrupting the membrane. Therefore, the development of biomimetic membrane assemblies allows the study of different biological processes in which cell membranes play an important role, and the characterization and screening of drug delivery tools and other membrane-bound components.
Since its development, membrane assemblies on planar silica surfaces have been the method of choice to study membrane-associated and membrane-bound components. However, the screening process of planar-substrate supported membranes has some limitations, as they rely on non-high-throughput or multiplexable technologies, like microscopy or Surface Plasmon Resonance (SPR). This results in time consuming studies, high cost, and high variability from sample to sample. Another biomimetic assembly commonly used are giant unilamellar vesicles (GUVs), which has proven to be valuable, as it better mimics the size and shape of cell membranes. Nevertheless, their assembly is time consuming and presents polydispersity.
The need of a biomimetic platform amenable to high-throughput screening process inspired the development of silica microsphere-supported membranes, as an alternative to planar-supported membranes and GUVs. Microsphere-supported membranes can be screened using flow cytometry, which is a laser-based high-throughput technology that measures several thousand particles and their physical characteristics in a few seconds. Moreover, flow cytometry has the advantage of being highly sensitive, accurate, reproducible, and it uses small sample volumes, making the screening process faster and more affordable.
To that end, we built and characterized multiplexable biomimetic membranes on silica microspheres for flow-based screening applications. Furthermore, we demonstrated that this new biomimetic construct could potentially constitute a more effective way of performing target based screening assays for membrane-bound components. We used microsphere-supported biomimetic membranes to screen: 1) membrane-protein interactions, 2) membrane disruption assays, and 3) polymer membrane interactions. Future areas for application of these methods are in areas such as, drug screening, antimicrobial peptide screening, and protease assay development.
Advisors/Committee Members: Andrew P. Shreve, Steven G. Graves, Gabriel A. Montaño, Deborah G. Evans.

Fernandez Oropeza, N. P. (2017). Development of biomimetic membrane assemblies on microspheres for high-throughput and multiplexable studies. (Doctoral Dissertation). University of New Mexico. Retrieved from https://digitalrepository.unm.edu/bme_etds/17

Fernandez Oropeza NP. Development of biomimetic membrane assemblies on microspheres for high-throughput and multiplexable studies. [Internet] [Doctoral dissertation]. University of New Mexico; 2017. [cited 2020 Jun 07].
Available from: https://digitalrepository.unm.edu/bme_etds/17.

Council of Science Editors:

Fernandez Oropeza NP. Development of biomimetic membrane assemblies on microspheres for high-throughput and multiplexable studies. [Doctoral Dissertation]. University of New Mexico; 2017. Available from: https://digitalrepository.unm.edu/bme_etds/17

► Atrial fibrillation (AF) is the disordered activation of the atrial myocardium, which is a major cause of stroke. Currently, the most effective, minimally traumatic…
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▼ Atrial fibrillation (AF) is the disordered activation of the atrial myocardium, which is a major cause of stroke. Currently, the most effective, minimally traumatic treatment for AF is percutaneous catheter ablation to isolate arrhythmogenic areas from the rest of the atrium. The standard in vitro evaluation of ablation catheters through lesion studies is a resource intensive effort due to tissue variability and visual measurement methods, necessitating large sample sizes and multiple prototype builds. A computational test bed for ablation catheter evaluation was built in SolidWorks® using the morphology and dimensions of the left atrium adjacent structures. From this geometry, the physical model was built in COMSOL Multiphysics®, where a combination of the laminar fluid flow, electrical currents, and bioheat transfer was used to simulate radiofrequency (RF) tissue ablation. Simulations in simplified 3D geometries led to lesions sizes within the reported ranges from an in-vivo ablation study. However, though the ellipsoid lesion morphologies in the full atrial model were consistent with past lesion studies, perpendicularly oriented catheter tips were associated with decreases of -91.3% and -70.0% in lesion depth and maximum diameter. On the other hand, tangentially oriented catheter tips produced lesions that were only off by -28.4% and +7.9% for max depth and max diameter. Preliminary investigation into the causes of the discrepancy were performed for fluid velocities, contact area, and other factors. Finally, suggestions for further investigation are provided to aid in determining the root cause of the discrepancy, such that the test bed may be used for other ablation catheter evaluations.
Advisors/Committee Members: David Clague.

► Current total knee arthroplasty (TKA) evaluation methods are both time consuming and expensive. They require fabrication of the TKA and then utilize a wear or…
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▼ Current total knee arthroplasty (TKA) evaluation methods are both time consuming and expensive. They require fabrication of the TKA and then utilize a wear or cadaveric simulator which does not necessarily replicate in-vivo conditions. Other analysis methods involve following the long-term success of TKA in subjects for five or more years. Mathematical modeling of TKA provide an efficient method at a greatly reduced cost for evaluating TKA. Obviously, the accuracy of a mathematical model is extremely important to the validity of the results.
Mathematical modeling of the knee faces many difficulties. The number of muscles actuating the knee is much larger than the number of equations of motion, producing an indeterminate system. Furthermore, the complex shapes of both the tibial plateaus and femoral condyles result in interactions which must be modeled using non-holonomic constrains. A forward solution mathematical model has been developed which overcomes these difficulties to serve as a theoretical simulator.
In this model, the articulating geometry of the TKA is defined mathematically. The trochlear groove, medial and lateral polyethylene plateaus, and post (in posterior stabilized designs) are defined using mathematical surfaces. Then, the femoral condyles, the patella surface, and the cam (in posterior stabilized designs) are defined using point clouds. Contact forces are computed by searching for contact between the defined surfaces and point clouds. The muscle forces are computed using control systems to generate the desired motion of the knee.
In addition the model, a graphical user interface (GUI) was developed which allows users to efficiently set up simulations for the model. This program guides the users step-by-step through mathematically defining the surfaces, selecting the orientation of the implants on the bones, and setting up initial conditions. It also gives users the option to adjust patient specific parameters such as ligament origins, insertions, and stiffness.
Using this model, many simulations have been performed to explore the effect of varying implant designs. With the knowledge gained from these designs, a new TKA was developed. A desired kinematic profile was selected, and the TKA was modified based on the results of successive simulations until the desired results were obtained.

► Mechanical conditioning has been shown to promote tissue formation in a wide variety of tissue engineering efforts. However the underlying mechanisms by which external…
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▼ Mechanical conditioning has been shown to promote tissue formation in a wide variety of tissue engineering efforts. However the underlying mechanisms by which external mechanical stimuli regulate cells and tissues are not known. This is particularly relevant in the area of heart valve tissue engineering (HVTE) owing to the intense hemodynamic environments that surround native valves. Some studies suggest that oscillatory shear stress (OSS) caused by steady flow and scaffold flexure play a critical role in engineered tissue formation derived from bone marrow derived stem cells (BMSCs). In addition, scaffold flexure may enhance nutrient (e.g. oxygen, glucose) transport. In this study, we computationally quantified the i) magnitude of fluid-induced shear stresses; ii) the extent of temporal fluid oscillations in the flow field using the oscillatory shear index (OSI) parameter, and iii) glucose and oxygen mass transport profiles. Noting that sample cyclic flexure induces a high degree of oscillatory shear stress (OSS), we incorporated moving boundary computational fluid dynamic simulations of samples housed within a bioreactor to consider the effects of: 1) no flow, no flexure (control group), 2) steady flow-alone, 3) cyclic flexure-alone and 4) combined steady flow and cyclic flexure environments. We also coupled a diffusion and convention mass transport equation to the simulated system. We found that the coexistence of both OSS and appreciable shear stress magnitudes, described by the newly introduced parameter OSI-t , explained the high levels of engineered collagen previously observed from combining cyclic flexure and steady flow states. On the other hand, each of these metrics on its own showed no association. This finding suggests that cyclic flexure and steady flow synergistically promote engineered heart valve tissue production via OSS, so long as the oscillations are accompanied by a critical magnitude of shear stress. In addition, our simulations showed that mass transport of glucose and oxygen is enhanced by sample movement at low sample porosities, but did not play a role in highly porous scaffolds. Preliminary in-house in vitro experiments showed that cell proliferation and phenotype is enhanced in OSI-t environments.
Advisors/Committee Members: Sharan Ramaswamy, Vinu Unnikrishnan, Nikolaos Tsoukias, Jorge Riera, Cheng-Xian Lin.

► The delivery of oxygen, nutrients, and the removal of waste are essential for cellular survival. Culture systems for 3D bone tissue engineering have addressed…
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▼ The delivery of oxygen, nutrients, and the removal of waste are essential for cellular survival. Culture systems for 3D bone tissue engineering have addressed this issue by utilizing perfusion flow bioreactors that stimulate osteogenic activity through the delivery of oxygen and nutrients by low-shear fluid flow. It is also well established that bone responds to mechanical stimulation, but may desensitize under continuous loading. While perfusion flow and mechanical stimulation are used to increase cellular survival in vitro, 3D tissue-engineered constructs face additional limitations upon in vivo implantation. As it requires significant amounts of time for vascular infiltration by the host, implants are subject to an increased risk of necrosis. One solution is to introduce tissue-engineered bone that has been pre-vascularized through the co-culture of osteoblasts and endothelial cells on 3D constructs.
It is unclear from previous studies: 1) how 3D bone tissue constructs will respond to partitioned mechanical stimulation, 2) how gene expression compares in 2D and in 3D, 3) how co-cultures will affect osteoblast activity, and 4) how perfusion flow will affect co-cultures of osteoblasts and endothelial cells. We have used an integrated approach to address these questions by utilizing mechanical stimulation, perfusion flow, and a co-culture technique to increase the success of 3D bone tissue engineering. We measured gene expression of several osteogenic and angiogenic genes in both 2D and 3D (static culture and mechanical stimulation), as well as in 3D cultures subjected to perfusion flow, mechanical stimulation and partitioned mechanical stimulation. Finally, we co-cultured osteoblasts and endothelial cells on 3D scaffolds and subjected them to long-term incubation in either static culture or under perfusion flow to determine changes in gene expression as well as histological measures of osteogenic and angiogenic activity.
We discovered that 2D and 3D osteoblast cultures react differently to shear stress, and that partitioning mechanical stimulation does not affect gene expression in our model. Furthermore, our results suggest that perfusion flow may rescue 3D tissue-engineered constructs from hypoxic-like conditions by reducing hypoxia-specific gene expression and increasing histological indices of both osteogenic and angiogenic activity.
Future research to elucidate the mechanisms behind these results may contribute to a more mature bone-like structure that integrates more quickly into host tissue, increasing the potential of bone tissue engineering.
Advisors/Committee Members: Seth W Donahue, Jeremy Goldman.

► Disuse osteoporosis is a condition in which reduced mechanical loading (e.g. bed-rest, immobilization, or paralysis) results in unbalanced bone turnover. The American black bear…
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▼ Disuse osteoporosis is a condition in which reduced mechanical loading (e.g. bed-rest, immobilization, or paralysis) results in unbalanced bone turnover. The American black bear is a unique, naturally occurring model for the prevention of disuse osteoporosis. Bears remain mostly inactive for up to half a year of hibernation annually, yet they do not lose bone mechanical strength or structural properties throughout hibernation. The long-term goal of this study is to determine the biological mechanism through which bears maintain bone during hibernation. This mechanism could pinpoint new signaling pathway targets for the development of drugs for osteoporosis prevention. In this study, bone specific alkaline phosphatase (BSALP), a marker of osteoblast activity, and tartrate resistant acid phosphatase (TRACP), a marker of osteoclast number, were quantified in the serum of hibernating and active black bears. BSALP and TRACP decreased during hibernation, suggesting a balanced reduction in bone turnover. This decrease in BSALP and TRACP were correlated positively to serum adiponectin and inversely to serum neuropeptide Y, suggesting a possible role of these hormones in suppressing bone turnover during hibernation. Osteocalcin (OCN) and undercarboxylated OCN increased dramatically in the serum of hibernating bears. These increases were inversely correlated with adiponectin, glucose, and serotonin, suggesting that OCN may have a unique role in energy homeostasis during hibernation. Finally, MC3T3-E1 osteoblasts were cultured in the serum from active and hibernating bears, and seasonal cell responses were quantified. Cells cultured in serum from hibernating bears had a reduced caspase-3/7 response, and more living cells, after apoptotic threat. The caspase-3/7 response was positively correlated to serum adiponectin and to gene expression of OCN and Runx2, suggesting that reduced caspase-3/7 activity may be related to the reduced differentiation potential of osteoblasts in hibernation serum, and that adiponectin is a potential effector hormone. In summary, the activities of osteoblasts and osteoclasts are reduced during hibernation in bears. This reduced turnover is due, in part, to hormonal control. Further study of potential effectors adiponectin and neuropeptide Y may provide insight into the biological mechanism through which bears maintain bone throughout hibernation.
Advisors/Committee Members: Seth W Donahue.

► Nearly half of the US population faces the risk of developing knee osteoarthritis (OA). Both <i>in vitro</i> and <i>in vivo</i> studies can aid in…
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▼ Nearly half of the US population faces the risk of developing knee osteoarthritis (OA). Both <i>in vitro</i> and <i>in vivo</i> studies can aid in a better understanding of the etiology, progression, and advancement of this debilitating disorder. The knee menisci are fibrocartilagenous structures that aid in the distribution of load, attenuation of shock, alignment and lubrication of the knee. Little is known about the biochemical and morphological changes associated with knee menisci following altered loading and traumatic impaction, and investigations are needed to further elucidate how degradation of this soft tissue advances over time. The biochemical response of porcine meniscal explants was investigated following a single bout of dynamic compression with and without the treatment of the pharmaceutical drug, anakinra (IL-1RA). Dynamic loading led to a strain-dependent response in both anabolic and catabolic gene expression of meniscal explants. By inhibiting the Interleukin-1 pathway with IL-1RA, a marked decrease in several catabolic molecules was found. From these studies, future developments in OA treatments may be developed. The implementation of an <i>in vivo</i> animal model contributes to the understanding of how the knee joint behaves as a whole. A novel closed-joint <i>in vivo</i> model that induces anterior cruciate ligament (ACL) rupture has been developed to better understand how traumatic injury leads to OA. The menisci of knees from three different groups (healthy, ACL transected, and traumatically impacted) were characterized using histomorphometry. The acute and chronic changes within the knee following traumatic impaction were investigated. The works presented in this dissertation have focused on the characterization, implementation, and development of mechanically-induced changes to the knee menisci.
Advisors/Committee Members: Tammy Lynn Haut Donahue.